This K01 award will provide the training and mentored research experience needed for me to become an independent researcher with a focus on improving the health outcomes of patients with or at risk for chronic viral infections. Chronic hepatitis C virus (HCV) infection affects over 3 million people in the U.S., with an estimated 80,000 HCV-related deaths per year. The health impacts of HCV are more severe in human immunodeficiency virus (HIV) patients, in whom HCV-associated liver disease is the leading cause of non-AIDS-related death. HIV/HCV coinfection has also been linked to an increased risk of extrahepatic outcomes, including cardiovascular and kidney disease. With the emergence of interferon-free regimens, most HCV patients can now be cured, regardless of HIV status. However, critical questions remain about 1) the effect of the timing of HCV treatment on HCV-related outcomes and 2) ongoing risk for HCV-related outcomes after HCV cure. This proposal addresses these pressing clinical questions with a focus on HIV/HCV-coinfected patients. The high-risk population of HIV/HCV- coinfected patients is ideal for investigating these questions for two reasons. First, because HIV/HCV- coinfected patients are a priority group for HCV treatment, they will have been treated over a range of liver disease stages, offering a unique opportunity to investigate the risks of treatment deferral. Second, ongoing risk of HCV-related outcomes after HCV cure may be more readily detectable in HIV/HCV- coinfected patients, who may experience lasting damage from increased immune activation and inflammation during HIV/HCV coinfection. The proposed research will consist of cohort studies among members of Kaiser Permanente Northern California. The strengths of this setting include a diverse and generalizable population of 3.3 million members, internal HCV-monoinfected and HIV-monoinfected comparison groups, and extensive clinical data from an electronic health record. The specific aims are to 1) determine the effect of early versus deferred HCV treatment on hepatic and extrahepatic outcomes among HIV/HCV-coinfected and HCV-monoinfected patients, and 2) evaluate the risk of hepatic and extrahepatic outcomes among HIV/HCV-coinfected and HCV-monoinfected patients after HCV cure, and in a matched group of HIV patients who never had HCV infection. The proposed research will be strengthened by the use of methods such as marginal structural models that overcome limitations of standard approaches. This career development award will provide training in the following areas: 1) epidemiology and pathogenesis of HCV infection and HIV/HCV coinfection, 2) HIV and liver- related outcomes, 3) clinical management of HCV and HIV/HCV patients, and 4) advanced biostatistical methods with an emphasis on causal inference. This mentored research and training will directly inform the clinical care of HIV/HCV patients and establish my career as an independent researcher in the field.